The present invention relates to a process for the preparation of pellets with a content of up to 90 wt. % of a pharmaceutical active ingredient having an extremely high solubility in water, by aqueous moist extrusion and subsequent spheronization.
Extrusion and subsequent spheronization is a long-known method for the preparation of granules having a defined shape and particle size which has also gained great importance in the production of pharmaceutical pellets (J. W. Conine et al., Drug and Cosmetic Ind. 106, 38-41 (1970)). At the same time the processing of numerous pharmaceutical active ingredients has also been described. Such multiparticulate forms of administration are often preferred to monolithic dosage forms due to improved bioavailability, pharmaceutical safety and reliability of action. Moreover, there exists a comprehensive body of literature dealing with optimizing the conditions of preparation, with the effect of the composition of the formulation and with the differences between various types of extruder as well as with the principles of extrusion/spheronization (L. Hellen et al., Int. J. Pharm., 95, 197-204 and 205-216 (1993); L. Baert et al., Int. J. Pharm., 96, 225-229 (1993) and Int. J. Pharm., 81, 225-223 (1992) and Int. J. Pharm., 97, 79-92 (1993); K. Thoma et al., Drug Dev. Ind. Pharm., 24 (5), 401-411 (1998)).
The advantages of extrusion/spheronization over pelletizing in the preparation of pellets include, among other factors, a greater compression of the pellets. Because of this, homogeneous pellets having a high content of active ingredients, that is, a content of active ingredients of up to 90 wt. %, can be obtained by the aforementioned method. Moreover, the pellets prepared by extrusion/spheronization are not only denser, but the surface of the pellets also has a lower porosity, so that the amount of functional films applied to the pellets can be distinctly decreased and more even release profiles can be achieved (G. Zhang et al., Drug Dev. Ind. Pharm., 16 (7), 1171-1184 (1990)). For this reason the preferred method for the preparation of pellets, in particular for the preparation of high-dosage pellets which are provided with coatings having a controlled-release action, is by extrusion/spheronization.
Besides the so-called melt extrusion, extrusion of granules moistened with water is one of the most common extrusion methods. In this process the active ingredients together with the auxiliary substances are granulated with the addition of water and then extruded, after which the extrudates are rounded in a spheroniser and dried. This method has the advantage over melt extrusion that it avoids undesirable heat load on the mixtures containing the active ingredients.
While pellets having a high content of active ingredients of up to 90 wt. %, even for active ingredients with a good to very good solubility in water, can be prepared by melt extrusion (WO 96/14059), the limit on the content of active ingredients in pellets prepared by the aqueous extrusion methods depends critically on the degree of water-solubility of the active ingredient. Thus, for example, for active ingredients having low to poor solubility in water, pellets are known with active ingredient contents of more than 80 wt. %, the pellets still being sufficiently round and having a narrow particle size distribution despite the low content of auxiliary substances (G. A. Hileman et al., Drug Dev. Ind. Pharm., 19 (4), 483-491 (1993)). However, it is well known in the art that the higher the water-solubility of the active ingredients, the lower the quantity of active ingredient which can be incorporated into the pellets (J. M. Newton et al., Pharm. Research, 509-514 (1998); P. H. Harrison, J. Pharm. Pharmacol., 37, 686-691 (1985)). Accordingly, in the case of readily water-soluble active ingredients having a solubility in water of 0.3 g/ml, generally only pellets having an active ingredient content of at most 60 wt. % can be satisfactorily prepared by means of aqueous moist extrusion.
Accordingly, it is the object of the present invention to provide pellets containing very highly water-soluble, pharmaceutical ingredients, that is, those having a solubility in water of xe2x89xa70.5 g/ml, preferably xe2x89xa71 g/ml, which pellets are prepared by means of the aqueous moist extrusion process and, advantageously, have not only a defined particle size and very good roundness, but also a relatively narrow particle size spectrum.
This object is achieved by the process according to the invention for the preparation of pellets containing xe2x89xa750 wt. % of a pharmaceutical active ingredient having a solubility in water of xe2x89xa70.5 g/ml, by granulating the mixture containing the active ingredient with water, extruding, rounding and drying the resulting moist pellets, which is characterised in that the mixture containing the active ingredient consists of:
A) at least 50 wt. %, preferably at least 65 wt. %, of at least one active ingredient having a solubility in water of  greater than 0.5 g/ml, preferably  greater than 1 g/ml, and
B) at most 50 wt. %, preferably at most 35 wt. %, of the combination of
a) microcrystalline cellulose having an average particle size of 15 to 25 xcexcm, determined by laser diffraction (Malvern Master Sizer) and
b) low-substituted hydroxypropyl cellulose having an average particle size in the range of 10 to 25 xcexcm, measured by laser diffraction,
the weight ratio of a):b) being in the range of 4:6 to 6:4 and the amount of water worked into the mixture being only so much that the mixture has an adequate plasticity for extrusion and spheronization.
The term xe2x80x9clow-substituted hydroxypropyl cellulosexe2x80x9d is used as as defined in U.S. Pharmacopeia and National Formulary, USP 24xe2x80x94NF 19, page 2466 (1999) and refers to a substituted hydroxypropyl ether of cellulose which when dried at 105xc2x0 for one hour contains not less than 5% nor more than 16% hydroxypropoxy groups.
The process according to the invention makes it possible to prepare pellets containing up to 90 wt. % of an active ingredient having extremely high solubility in water, that is, a solubility in water of at least 0.5 g/ml, such as, for example, tramadol hydrochloride (solubility greater than 3.0 g/ml), chlorpromazine hydrochloride (solubility 2.5 g/ml), metamizol-Na (solubility greater than 1 g/ml), or diphenhydramine hydrochloride (solubility 860 mg/ml).
It is essential to the process according to the invention that the auxiliary substances used, namely, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, have a certain average particle size and are used in a certain weight ratio to one another. Thus one must use a microcrystalline cellulose having an average particle size of 15 to 20 xcexcm, such as, for example, Avicel(trademark) PH 105 or Emcocel SP 15(trademark), or low-substituted hydroxypropyl cellulose having an average particle size in the range of 10 to 25 xcexcm, such as, for example, 1-HPC LH 31(trademark), 1-HPC LH 32(trademark) or 1-HPC LH 41(trademark), preferably having a particle size of xe2x89xa620 xcexcm (for example, 1-HPC LH 32(trademark), 1-HPC LH 30(trademark) or 1-HPC LH 41(trademark)) and a hydroxypropyl content of 10 to 13 wt. % (1-HPC LH 31).
The comparison tests show that when the hitherto preferably used microcrystalline cellulose having a particle size of approximately 50 xcexcm is used in the preparation, moist extrusion of pellets containing very readily water-soluble active ingredients such as tramadol hydrochloride, can produce only pellets with an active ingredient content of at most 40 to 45 wt. % in useful yield. Higher contents of active ingredients result in agglomeration or scarcely roundable rods of extrudate (dumb-bells) having a high dust content, depending on the quantity of water present. Surprisingly, this disadvantage can successfully be surmounted by the auxiliary substances used according to the invention.
The proportion of these auxiliary substances in the mixture containing active ingredients should be 10 to 50 wt. %, preferably from 20 to 30 wt. %, and a ratio of microcrystalline cellulose to low-substituted hydroxypropyl cellulose of 4:6 to 6:4, preferably 1:1, particularly preferably 5.1:4.9, should be maintained.
Persons skilled in the art are familiar with the remaining conditions of the process, such as the adjustment of the duration, speed and loading during the spheronization depending on the moisture content of the extrudates, the choice of the type of extruder and the spheronization conditions.
The pellets prepared by the process according to the invention initially have no controlled-release action for the incorporated highly water-soluble active ingredients. However, despite the high tendency of low-substituted hydroxypropyl cellulose to disintegrate, the pellets show no disintegration even after release of the active ingredient and residence for several hours in physiological release media. They are therefore ideal substrates to be covered with functional coatings such as, for example, coatings having controlled-release action and/or coatings which are resistant to gastric juices. It is also possible to mold the coated pellets to form rapidly disintegrating tablets, optionally in combination with uncoated pellets as an initial dose. The advantage of the formulation lies in the incorporation of high quantities of active ingredients despite their high solubility in water. Because of this, high dosages of the incorporated active ingredient can be administered in the form of small capsules or tablets, which are generally more pleasant for patients to take.
The invention accordingly also provides processes for the preparation of pellets having coatings having controlled-release action and/or which are resistant to gastric juices, optionally molded to form tablets or enclosed in capsules, by providing the pellets prepared according to the invention with appropriate coatings after preparation.
All pharmaceutically safe coating materials which are known to the person skilled in the art are suitable for use as coating materials. Preferably natural, optionally modified or synthetic polymers are used as coating materials. These are polymers such as, for example, cellulose ethers or acrylic resins. Cellulose derivatives which are insoluble in water or swellable in water are especially preferred, such as alkyl cellulose, preferably ethyl cellulose, or acrylic resins which are insoluble in water, such as poly(meth)acrylic acid and/or its derivatives, such as its salts, amides or esters. Waxes which are insoluble in water can also be used as coating materials.
These materials are known in the art, for example, Bauer, Lehmann, Osterwald, Rothgang, xe2x80x9cxc3x9cberzogene Arzneiformenxe2x80x9d, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998, page 69 ff. and are hereby incorporated by reference.
In addition to the polymers and waxes which are insoluble in water, optionally in order to adjust the release rate of the active ingredient, concomitant use may also be made of preferably up to 30 wt. % of preferably water-soluble polymers without controlled-release action, such as, for example, polyvinylpyrrolidone, or water-soluble cellulose derivatives, such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose or hydroxypropyl cellulose, optionally in combination with known plasticizers.
The formulations containing active ingredients may also be provided with further coatings in addition to the controlled-release coating. In this connection, for example, a coating composed of a material which is different from the material of the controlled-release coating can be applied to the substrate surface as a separating layer without controlled-release action. Suitable covering materials for this separating layer are preferably cellulose, polyvidones, polyacrylates or even natural polymeric materials.
It is also possible to make the further coatingxe2x80x94preferably over the coating having controlled-release actionxe2x80x94out of the active ingredient of the substrates or out of an active ingredient which is different from these, from which this active ingredient can be released uncontrolled after oral administration. By means of this multilayered coating, after the administration of the preparation an initial dose can be made available very rapidly for the initial therapy, with the level of the active ingredient being maintained through the subsequent controlled-release administration of the active ingredient. Suitable coating materials for this are pharmaceutically safe materials in combination with the initial active ingredient such as, for example, cellulose ethers, polyvidones or polyacrylates. But it is also possible to provide yet another pharmaceutically active ingredient in the non-controlled release coating in addition to or instead of the substrate active ingredient or in addition to or instead of the aforementioned, preferably opioid, active ingredient which is different from the substrate active ingredient.
In addition, besides the coating having controlled-release action, the pellets may also have other coatings whose solubility is pH-dependent. In this way it is possible to assure, for example, that at least a portion of the pellets of a preparation pass through the gastric tract without being released, and that the active ingredients are first released in the intestinal tract.